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. 2025 Jul;122(26):e2410229122.
doi: 10.1073/pnas.2410229122. Epub 2025 Jun 23.

Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling

Nihel Berrebeh  1   2 , Yvon Mbouamboua  3 , Raphaël Thuillet  1   2 , Mina Ottaviani  1   2 , Fabien Robert  1   2 , Mustapha Kamel Chelgham  1   2 , Virginie Magnone  3 , Agnès Desroches-Castan  4 , Nicolas Ricard  4 , Ignacio Anegon  5 , Séverine Remy  5 , Ralph Theo Schermuly  6 , Kevin Lebrigand  3 , Baktybek Kojonazarov  6 , Laurent Savale  1   2   7 , Marc Humbert  1   2   7 , Sabine Bailly  4 , Pascal Barbry  3   8 , Ly Tu #  1   2 , Christophe Guignabert #  1   2
Affiliations

Bone morphogenetic protein-9 controls pulmonary vascular growth and remodeling

Nihel Berrebeh et al. Proc Natl Acad Sci U S A. 2025 Jul.

Abstract

Pulmonary arterial hypertension (PAH) and hereditary hemorrhagic telangiectasia (HHT) are two distinct vascular diseases linked to impaired signaling through bone morphogenetic protein (BMP) receptor complexes in endothelial cells. Although BMP-9 plays a central role in activating this pathway by binding to ALK1 and BMPR-II, its precise function in the pulmonary microvasculature has remained unclear. In this study, we demonstrate a role for BMP-9 in regulating pulmonary vascular architecture and homeostasis. Our findings reveal that BMP-9 signaling intersects with VEGF pathways and contributes to the delicate balance between vascular growth and remodeling in the lungs. We also show that disruption of this pathway can shift vascular responses toward an HHT-like state, potentially altering disease susceptibility. These insights offer a unique perspective on how BMP-9 and ALK1 shape pulmonary vascular biology and suggest that targeting this axis could inform future strategies for treating complex vascular diseases such as PAH.

Keywords: ALK1; VEGF; pulmonary hypertension; pulmonary microvasculature; pulmonary vascular remodeling.

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Conflict of interest statement

Competing interests statement:Over the last three years, C.G. reports grants from Acceleron Pharma (Cambridge, MA), a wholly-owned subsidiary of Merck & Co., Inc. (Rahway, NJ), MSD, Corteria, Structure therapeutics (ex ShouTi), and Diagonal Therapeutics, outside the submitted work. M.H. reports grants and personal fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX and United Therapeutics, outside the submitted work. Over the last three years, C.G. reports grants from Acceleron Pharma (Cambridge, MA), a wholly-owned subsidiary of Merck & Co., Inc. (Rahway, NJ), MSD, Corteria, Structure therapeutics (ex ShouTi), and Diagonal Therapeutics, outside the submitted work. M.H. reports grants and personal fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX and United Therapeutics, outside the submitted work.

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